Use of drugs for hypertension or heart failure and the risk of death in COVID-19: association with loop-diuretics.

PURPOSE: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. METHODS: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. RESULTS: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17-1.35] and thiazides with reduced risk (0.78; 0.69-0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. CONCLUSION: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation.

Assessing Safety of Direct Thrombin Inhibitors, Direct Factor Xa Inhibitors and Vitamin K Antagonists in Patients with Atrial Fibrillation: A Nation-Wide Propensity Score Matched Cohort from Sweden.

PURPOSE: To evaluate associations between first-time use of direct oral anticoagulants or vitamin K antagonists and bleeding risk or mortality in the elderly with atrial fibrillation in a real-world setting in Sweden. PATIENTS AND METHODS: The study population comprises first-time users, above age 60, of dabigatran, apixaban, rivaroxaban, or warfarin, with first atrial fibrillation occurrence within 6 months before dispensing (2012-2016). Outcomes were gastrointestinal, any, or intracranial bleeding, and mortality. Exposure started at first dispensing of a study drug. Follow-up continued until outcome, end of drug supply, dispensing of another study drug, death or end of study (December 2016). We conducted a propensity score matched, nationwide register-based cohort study including three treatment groups: direct thrombin inhibitors, direct factor Xa inhibitors and vitamin K antagonists, each compared to the other two, focusing on subgroups of age and sex. Cox proportional hazard models adjusted for CHA2DS2VASc and HAS-BLED scores provided hazard ratios with 95% confidence intervals. RESULTS: The matched study populations consisted of 7,264 patients for the direct thrombin inhibitors vs vitamin K antagonists comparison, 12,566 patients for the direct factor Xa inhibitors vs vitamin K antagonists comparison and 6,606 patients for the direct factor Xa inhibitors vs direct thrombin inhibitors comparison, in total 26,436 patients. Numerically high, but imprecise, hazard ratios for gastrointestinal bleeding were observed for women aged 75-80, 80-85, or above 85 years, eg 6.00 (1.02, 113.47) for direct thrombin inhibitors vs vitamin K antagonists. For both sexes, numerically high hazard ratios for any bleeding were observed in ages 80-85, or above 85 years, eg 2.90 (1.01, 10.41) for direct thrombin inhibitors vs vitamin K antagonists. Numerically high HRs for intracranial bleeding were observed for women aged 75-80 or 80-85 years, eg 2.70 (0.65, 18.19) for direct factor Xa inhibitors vs vitamin K antagonists. Excess mortality was observed in both sexes, across age groups, for naive and experienced anticoagulant users. CONCLUSION: The observed increased gastrointestinal bleeding risk in first-time users of direct thrombin inhibitors or direct factor Xa inhibitors is consistent with previous studies. The possible risk of excess mortality merits further studies.

Drug use and torsades de pointes cardiac arrhythmias in Sweden: a nationwide register-based cohort study.

OBJECTIVE: To study the occurrence of torsades de pointes (TdP) ventricular tachycardia in relation to use of drugs labelled with TdP risk, using two nationwide Swedish registers. DESIGN: Prospective register-based cohort study. SETTING: Entire Sweden. PARTICIPANTS: Persons aged ≥18 years prescribed and dispensed any drug classified with TdP risk during 2006-2017, according to CredibleMeds. Persons with a registered TdP diagnosis during the study period, using drugs labelled with known (TdP 1), possible (TdP 2) or conditional (TdP 3) risk at the incident of TdP were examined. PRIMARY OUTCOME MEASURES: Occurrence of TdP in relation to exposure rates for individual drugs with TdP risk. SECONDARY OUTCOME MEASURES: Concurrent use of more than one TdP-labelled drug in a person with a TdP diagnosis. RESULTS: During the study period, 410 TdP cases using drugs with TdP risk labels at the incident were registered; 205 women and 205 men, mean age 74.0 and 71.5 years, respectively. Antidepressants dominated (129/410, 30%), followed by antiarrhythmics (17%). Diuretics and gastric acid-secretion inhibitors, with TdP risk related to induction of hypokalaemia or hypomagnesaemia, were used in 56% and 32% of the 410 TdP cases, respectively. Among the most used antidepressants, citalopram with known TdP 1 risk was associated with both a higher absolute number and incidence of TdP per 100 000 users (two to four times), compared with mirtazapine with possible (TdP 2), and sertraline with conditional (TdP 3) risk. Multiple risk factors, including advanced age, cardiovascular disease and treatment with more than one TdP-classified drug, were frequently observed. CONCLUSIONS: Antidepressants followed by antiarrhythmics dominated among TdP risk drugs used by adults with TdP diagnosis, the majority being ≥65 years. TdP risk class and concomitant medication should be considered when prescribing antidepressants to older patients.

Psychotropic drugs and the risk of fall injuries, hospitalisations and mortality among older adults.

OBJECTIVE: To investigate whether psychotropics are associated with an increased risk of fall injuries, hospitalizations, and mortality in a large general population of older adults. METHODS: We performed a nationwide matched (age, sex, and case event day) case-control study between 1 January and 31 December 2011 based on several Swedish registers (n = 1,288,875 persons aged ≥65 years). We used multivariate conditional logistic regression adjusted for education, number of inpatient days, Charlson co-morbidity index, dementia and number of other drugs. RESULTS: Antidepressants were the psychotropic most strongly related to fall injuries (ORadjusted : 1.42; 95% CI: 1.38-1.45) and antipsychotics to hospitalizations (ORadjusted : 1.22; 95% CI: 1.19-1.24) and death (ORadjusted : 2.10; 95% CI: 2.02-2.17). Number of psychotropics was associated with increased the risk of fall injuries, (4 psychotropics vs 0: ORadjusted : 1.53; 95% CI: 1.39-1.68), hospitalization (4 psychotropics vs 0: ORadjusted : 1.27; 95% CI: 1.22-1.33) and death (4 psychotropics vs 0: ORadjusted : 2.50; 95% CI: 2.33-2.69) in a dose-response manner. Among persons with dementia (n = 58,984), a dose-response relationship was found between number of psychotropics and mortality risk (4 psychotropics vs 0: ORadjusted : 1.99; 95% CI: 1.76-2.25). CONCLUSIONS: Our findings support a cautious prescribing of multiple psychotropic drugs to older patients. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons, Ltd.

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults - a Swedish nationwide study.

AIM: The aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. METHODS: A matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n = 286,092) and matched controls (n = 1,430,460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds (www.crediblemeds.org) and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. RESULTS: Use of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. CONCLUSION: The CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.

The use of central nervous system active drugs during pregnancy.

CNS-active drugs are used relatively often during pregnancy. Use during early pregnancy may increase the risk of a congenital malformation; use during the later part of pregnancy may be associated with preterm birth, intrauterine growth disturbances and neonatal morbidity. There is also a possibility that drug exposure can affect brain development with long-term neuropsychological harm as a result. This paper summarizes the literature on such drugs used during pregnancy: opioids, anticonvulsants, drugs used for Parkinson's disease, neuroleptics, sedatives and hypnotics, antidepressants, psychostimulants, and some other CNS-active drugs. In addition to an overview of the literature, data from the Swedish Medical Birth Register (1996-2011) are presented. The exposure data are either based on midwife interviews towards the end of the first trimester or on linkage with a prescribed drug register. An association between malformations and maternal use of anticonvulsants and notably valproic acid is well known from the literature and also demonstrated in the present study. Some other associations between drug exposure and outcome were found.

Effect of probenecid and quinidine on the transport of alovudine (3'-fluorothymidine) to the rat brain studied by microdialysis.

Microdialysis was used to sample extracellular unbound concentrations of alovudine in order to study the influence of well-known transport inhibitors (probenecid and quinidine) on the transport of alovudine between the blood and the brain extracellular fluid or whole brain tissue. The AUC (area under the time versus concentration curve) ratio brain extracellular fluid/serum was 0.17+/-0.036 after a subcutaneous injection of alovudine 25 mg/kg in rats treated with probenecid 25 mg/kg subcutaneous (n=5), which was not significantly different from the control group (AUC ratio 0.24+/-0.039). Perfusion through the microdialysis probe with probenecid 100 microM (n=4) also had no effect on the brain extracellular fluid/serum AUC ratio after alovudine 25 mg/kg subcutaneous. The AUC ratio brain extracellular fluid/serum was 0.085+/-0.009 after subcutaneous injection of alovudine 25 mg/kg in rats treated with quinidine 25 mg/kg intraperitoneally (n=8), which was significantly lower than the control group. However, the whole brain tissue concentration was not significantly different between control rats (n=5) and rats treated with quinidine (n=4) 1 hr after subcutaneous injection of alovudine 25 mg/kg (brain to serum ratios being 0.11+/-0.006 and 0.10+/-0.005 respectively). Finally, the microdialysis recovery of alovudine increased with increasing concentrations (10, 50, 250, 1250 microM) of alovudine in the perfusion fluid. The recovery of alovudine was increased in quinidine-treated rats but not in those given probenecid. Thus, probenecid does not significantly influence the concentration gradient of alovudine over the blood-brain barrier in the rat after systemic or after local administration, while quinidine lowered brain extracellular fluid concentration of alovudine, but not total brain tissue concentration. The mechanism behind this phenomenon is not yet known.